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Anti-VEGFR-3 antibody compositions
8481034 Anti-VEGFR-3 antibody compositions
Patent Drawings:

Inventor: Pytowski, et al.
Date Issued: July 9, 2013
Primary Examiner: Li; Ruixiang
Assistant Examiner:
Attorney Or Agent: Woods; Nicole S.Hason; Averie K.
U.S. Class: 424/143.1; 530/388.1
Field Of Search:
International Class: A61K 39/395; C07K 16/18
U.S Patent Documents:
Foreign Patent Documents: 02/060950
Other References: Persaud, et al., Involvement of the VEGF receptor 3 in tubular morphogenesis demonstrated with a human anti-human VEGFR-3 monoclonal thatantagonizes receptor activation by VEGF-C, J. Cell Sci. 117:2745-2756 (2004). cited by applicant.
Pytowski, et al., Complete and Specific inhibition of Adult Lymphatic Regeneration by a Novel VEGFR-3 Neutralizing Antibody, J. Nat. Cancer Inst., 97(1):14-21 (2005). cited by applicant.
Co, et al., Humanized antibodies for antiviral therapy, Proc. Natl. Acad. Sci. USA 88:2869-2873 (1991). cited by applicant.
Goldman, et al., Cooperative and redundant roles of VEGFR-2 and VEGFR-3 signaling in adult lymphangiogenesis, FASEB J. 21(4):1003-1012 (2007). cited by applicant.
Harlow and Lane (1988) Antibodies, A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, pp. 567-569, ISBN 0-87969-314-2. cited by applicant.
Ho, et al., Site-directed mutagenesis by overlap extension using the polymerase chain reaction, Gene 77:51-59 (1989). cited by applicant.
Holash, et al., Inhibitors of growth factor receptors, signaling pathways and angiogenesis as therapeutic molecular agents, Cancer Metastasis Rev. 25(2):243-252 (2006). cited by applicant.
Jimenez, et al., Generation of a recombinant fully human bifunctional antibody that neutralizes both vascular endothelial growth factor receptor 2 and 3, Proc. Amer. Assoc. Cancer Res. Abstract 2559, vol. 45 (2004); Available online at: toshow=&hits=10&RESULTFORMAT=&fulltext=JIMENEZ+&searchid=1&FIRSTINDEX=0&vo- lume=2004&issue=1&resourcetype=HWCIT. cited by applicant.
Jimenez, et al., A recombinant, fully human, bispecific antibody neutralizes the biological activities mediated by both vascular endothelial growth factor receptors 2 and 3, Mol Cancer Ther. 4(3):427-434. (2005). cited by applicant.
Kabat, et al., Sequences of Proteins of Immunological Interest, Fifth Edition, U. S. Department of Health and Human Services, NIH publication No. 91, 3242 (1991). cited by applicant.
Laakkonen, et al., Vascular Endothelial Growth Factor Receptor 3 Is Involved in Tumor Angiogenesis and Growth, Cancer Res. 67(2):593-599 (2007). cited by applicant.
Nilsson, et al., VEGF receptor 2/-3 heterodimers detected in situ by proximity ligation on angiogenic sprouts, EMBO J. 29(8):1377-1388 (2010). cited by applicant.
Pajusola, et. al., FLT4 Receptor Tyrosine Kinase Contains Seven Immunoglobulin-like Loops and Is Expressed in Multiple Human Tissues and Cell Lines, Cancer Res. 52:5738-5743 (1992). cited by applicant.
Persaud, et al., Generation and characterization of monoclonal antibodies that antagonize the binding of VEGF-C to VEGFR-3 (Flt-4), AACR Meeting Abstract 247, European J. Can., 38(Suppl 7):78-78 (2002). cited by applicant.
Remington: The Science and Practice of Pharmacy, 19th ed., vol. II, Part 7, pp. 1447-1676 (1995), A. Gennaro et al., Mack Publishing Co. cited by applicant.
Roberts, et al., Inhibition of VEGFR-3 Activation with the Antagonistic Antibody More Potently Suppresses Lymph Node and Distant Metastases than Inactivation of VEGFR-2, Cancer Res., 66(5):2650-2657 (2006). cited by applicant.
Wu, et al., Humanization of a Murine Monoclonal Antibody by Simultaneous Optimization of Framework and CDR Residues, J. Mol. Biol. 294:151-162 (1999). cited by applicant.
Zhang, et al., The VEGFR-3 Receptor Participates in Kaposi's Sarcoma Associated Virus (KSHV) / Human Herpes Virus 8 (HHV-8) Infection of Endothelial Cells, ASH meeting Abstract 993, Blood 102(11):279a (2003). cited by applicant.
Zhang, et al., Kaposi's Sarcoma Associated Virus Envelope Glycoprotein B Induces Endothelial Cell Migration and Proliferation by Activation of VEGFR-3 through Integrin a3beta1, ASH meeting Abstract 417, Blood 102(11): 122a-123a (2003). cited byapplicant.
Zhang, et al., Kaposi's Sarcoma-associated Herpesvirus Activation of Vascular Endothelial Growth Factor Receptor 3 Alters Endothelial Function and Enhances Infection, J Biol Chem. 280(28):26216-26224 (2005). cited by applicant.
Zhu, et al., Inhibition of Vascular Endothelial Growth Factor-induced Receptor Activation with Anti-Kinase Insert Domain-containing Receptor Single-Chain Antibodies from a Phage Display Library, Cancer Res. 58:3209-3214 (1998). cited byapplicant.

Abstract: The present invention provides anti-VEGFR-3 monoclonal antibodies, pharmaceutical compositions containing said antibodies and uses of said antibodies in the treatment of disease.
Claim: We claim:

1. An antibody or fragment thereof that binds to human VEGFR-3 comprising a LCDR1 of SEQ ID NO: 1, a LCDR2 of SEQ ID NO: 2, a LCDR3 of SEQ ID NO: 3, a HCDR1 of SEQ ID NO:6, a HCDR2 ofSEQ ID NO: 7 and a HCDR3 of SEQ ID NO: 8.

2. The antibody or fragment thereof of claim 1, comprising a light chain variable region of SEQ ID NO: 5 and a heavy chain variable region of SEQ ID NO: 10.

3. The antibody or fragment thereof of claim 2, wherein the antibody comprises a light chain of SEQ ID NO: 15 and a heavy chain of SEQ ID NO: 16.

4. The antibody or fragment thereof of claim 3, wherein the antibody comprises two light chains of SEQ ID NO: 15 and two heavy chains of SEQ ID NO: 16.

5. A pharmaceutical composition comprising the antibody or fragment thereof of claim 4 together with a pharmaceutically acceptable carrier, diluent or excipient.

6. A pharmaceutical composition of claim 5 comprising an additional pharmaceutical agent, wherein the agent is cisplatin, 5-fluorouracil, leucovorin, oxaliplatin or docetaxel.
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